TY - JOUR
T1 - The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis
AU - Winkler, Emma S.
AU - Shrihari, Swathi
AU - Hykes, Barry L.
AU - Handley, Scott A.
AU - Andhey, Prabhakar S.
AU - Huang, Yan Jang S.
AU - Swain, Amanda
AU - Droit, Lindsay
AU - Chebrolu, Kranthi K.
AU - Mack, Matthias
AU - Vanlandingham, Dana L.
AU - Thackray, Larissa B.
AU - Cella, Marina
AU - Colonna, Marco
AU - Artyomov, Maxim N.
AU - Stappenbeck, Thaddeus S.
AU - Diamond, Michael S.
N1 - Funding Information:
We thank M. Baldridge, D. Lenschow, and T. Morrison for providing mice and viruses. We also thank G. Randolph, U. Jain, and H. Miller for experimental advice, the Washington University Gnotobiotic Facility for assistance with germ-free experiments, B. Evans for mass spectrometry analysis, E. Lantelme for cell sorting, and S. Higgs for experimental and editorial advice. This work was supported by NIH grants R01 AI143673 , R01 AI127513 , R01 AI123348 , and T32 AI007163 .
Funding Information:
We thank M. Baldridge, D. Lenschow, and T. Morrison for providing mice and viruses. We also thank G. Randolph, U. Jain, and H. Miller for experimental advice, the Washington University Gnotobiotic Facility for assistance with germ-free experiments, B. Evans for mass spectrometry analysis, E. Lantelme for cell sorting, and S. Higgs for experimental and editorial advice. This work was supported by NIH grants R01 AI143673, R01 AI127513, R01 AI123348, and T32 AI007163. E.S.W. and S.S. performed and analyzed virus and bacteria burden in mice. E.S.W. evaluated immune responses. L.D. S.A.H. and B.L.H. performed bacteria 16S rRNA data analyses. A.S. P.S.A. and M.N.A. performed library preparation and RNA sequencing data analysis. K.K.C. performed mass spectrometry measurements. Y.-J.S.H. performed mosquito experiments with funding support from D.L.V. M.M. provided the anti-CCR2 mAb. E.S.W. and M.S.D. designed experiments with assistance from L.B.T. T.S.S. M. Cella, M. Colonna, and S.A.H. E.S.W. and M.S.D. wrote the initial draft of the manuscript. M.S.D. is a consultant for Inbios, Eli Lilly, Vir Biotechnology, NGM Biopharmaceuticals, and on the Scientific Advisory Board of Moderna. The Diamond laboratory has received unrelated funding under sponsored research agreements from Moderna and Emergent BioSolutions.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
AB - Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
KW - Clostridium
KW - alphavirus
KW - bile acid
KW - chikungunya
KW - interferon
KW - microbiome
KW - monocyte
KW - pathogenesis
KW - plasmacytoid dendritic cell
UR - http://www.scopus.com/inward/record.url?scp=85088558339&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.06.029
DO - 10.1016/j.cell.2020.06.029
M3 - Article
C2 - 32668198
AN - SCOPUS:85088558339
SN - 0092-8674
VL - 182
SP - 901-918.e18
JO - Cell
JF - Cell
IS - 4
ER -